Targeted photoacoustic imaging of VEGF receptors in angiogenic vasculature

血管生成血管系统中 VEGF 受体的靶向光声成像

• 批准号: 8126616
• 负责人: Joseph M Backer
• 金额: $ 28.69万
• 依托单位: SIBTECH, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8126616
• 关键词: Achievement; Acoustics; Affinity; Benign; Binding; Biological; Cancerous; Carbon Nanotubes; Computer software; Connecticut; Contrast Media; Cysteine; Dendrimers; Detection; Development; Diagnosis; Diagnostic; Diagnostic Neoplasm Staging; Discrimination; Dyes; Early Diagnosis; Endocytosis; Endothelial Cells; Engineering; Fluorescent Dyes; Goals; Gold; Heating; Hemoglobin; Image; Indocyanine Green; Lasers; Lesion; Light; Malignant - descriptor; Mediating; Modeling; Monitor; N-terminal; Nuclear; Phase; Physiologic pulse; Prevalence; Proteins; Resolution; Scanning; Signal Transduction; Silicon Dioxide; Site; Staging; Testing; Three-Dimensional Image; Tissues; Toxic effect; Tracer; Tumor stage; Ultrasonic wave; Ultrasonics; Universities; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factors; Vascular remodeling; absorption; base; chromophore; cost effective; data acquisition; experience; in vivo; innovation; interest; malignant breast neoplasm; mouse model; nanoparticle; novel; overexpression; pre-clinical; receptor; receptor mediated endocytosis; response; scaffold; targeted delivery; tool; tumor; vector

DESCRIPTION (provided by applicant): We propose to develop a contrast agent for photoacoustic imaging targeted to the receptors of vascular endothelial growth factor (VEGFR), so it can be accumulated and retained in tumor endothelial cells by VEGFR-mediated endocytosis. VEGFR are over expressed in angiogenic tumor vasculature from the very early stages of tumor development and therefore VEGFR imaging can be used for early diagnosis as well as for image-guided optimization and management of anti-angiogenic therapy. In order to enhance conversion of light into acoustic signal and increase the sensitivity of detection of abnormal levels of VEGFR in vivo by photoacoustic imaging, we will multiplex near-infrared fluorescent dye indocyanine green on a dendrimer scaffold, and then conjugate the derivatized dendrimer to VEGF. We will test this tracer for photoacoustic imaging of VEGFR in the established model of tumor vascular remodeling in response to anti-angiogenic therapy. For this project we combine the expertise and achievements of three groups, the experts in developing of targeted tracers for imaging of VEGFR in angiogenic vasculature, innovative imaging hardware and software for photoacoustic imaging of tumor lesions, and novel derivatives of ICG for imaging. This study will provide the first-in-class targeted PAI tracer and establish the feasibility of targeted photoacoustic imaging of VEGF receptors in tumor vasculature. If successful, might provide a safe and cost-effective alternative to nuclear imaging for cancerous lesions located at the depths less than 2-3 cm. In Phase II we will establish feasibility of this tracer for early diagnostic of relatively deep tumor lesions, discrimination of malignant and benign lesions, and perform late pre-clinical development of the tracer. PUBLIC HEALTH RELEVANCE: Receptors of vascular endothelial growth factor (VEGFR) are over expressed in angiogenic tumor vasculature from the very early stages of tumor development, therefore VEGFR imaging can be used for early diagnosis and image-guided optimization of anti-angiogenic therapy. We propose to develop a contrast agent for photoacoustic imaging that will be targeted to these receptors, so it can be accumulated and retained in tumor endothelial cells by specific receptor-mediated endocytosis. In order to enhance conversion of light into acoustic signal and increase the sensitivity of detection, we will multiplex a near-infrared fluorescent dye indocyanine green on a dendrimer scaffold, and then site-specifically conjugate the derivatized dendrimer to targeting protein, VEGF. We will test this tracer for photoacoustic imaging of VEGFR in the established model of tumor vascular remodeling in response to anti-angiogenic therapy. Thus study will provide the first-in-class targeted tracer for photoacoustic imaging of VEGFR, and might enable a safe, cost-effective alternative to nuclear imaging for detection of cancerous lesions located at the depths less than 2-3 cm.

描述（由申请人提供）：我们拟开发一种针对血管内皮生长因子（VEGFR）受体的光声成像造影剂，通过VEGFR介导的内吞作用在肿瘤内皮细胞中积累和保留。从肿瘤发展的早期开始，VEGFR就在血管生成肿瘤的血管系统中过度表达，因此VEGFR成像可以用于早期诊断以及图像引导的抗血管生成治疗的优化和管理。为了增强光到声信号的转换，提高光声成像检测体内VEGFR异常水平的灵敏度，我们将近红外荧光染料吲哚菁绿复染在树突支架上，然后将衍生的树突与VEGF偶联。我们将在抗血管生成治疗的肿瘤血管重塑模型中测试这种示踪剂对VEGFR的光声成像。在这个项目中，我们结合了三个小组的专业知识和成果，分别是开发血管生成血管中VEGFR成像的靶向示踪剂的专家，肿瘤病变光声成像的创新成像硬件和软件的专家，以及用于成像的新型ICG衍生物。本研究将提供国内首创的靶向PAI示踪剂，并建立肿瘤血管中VEGF受体靶向光声成像的可行性。如果成功，可能为深度小于2-3厘米的癌性病变提供一种安全、经济的替代核成像方法。在II期，我们将建立该示踪剂早期诊断相对深部肿瘤病变、区分恶性和良性病变的可行性，并进行示踪剂的后期临床前开发。